Evaluating the effect of adding risperidone to clozapine is an example of clinical practice getting out ahead of evidence and theory. It has become common practice, so we need to know the answer. The combination surely will add adverse effects, but what hypothesis supports the notion of increased efficacy? Clozapine has superior efficacy for psychosis in treatment-resistant patients and low occupancy (fast on/off) at the dopamine 2 receptor. Is this important for diminished motor adverse effects or for superior efficacy? If so, adding risperidone will terminate this advantage. I think this may be the case for adverse effects, but we tested the partial occupancy hypothesis and the D2/5HT ratio hypothesis for clozapine (Carpenter et al., 1998) and found that full D2 occupancy did not interfere with clozapine superiority. But in this analysis, we found no evidence that being on a drug with high affinity for the D2 receptor combined with clozapine gave any efficacy advantage and recommended against the practice.

To reason in the other direction, it is clear that risperidone has its best benefit/adverse effect profile at low doses. Combining risperidone with another antipsychotic could move that profile in an unfavorable direction.

But clinicians are stuck. In most patients, no matter what the pharmacotherapy, response is incomplete. It is understandable that doctors try “harder,” and increasing dose and polypharmacy seem the only way. When only first-generation drugs were available, this routinely lead to excessive doses with more adverse effects, poorer adherence, and no evidence for better efficacy. Are we now repeating this mistake with polypharmacy? This clozapine/risperidone report is well done, and the failure to observe an advantage for the combination should be a decisive influence on this common practice.

The paper by Honer et al., which reported a lack of benefit from augmentation of clozapine by risperidone in patients with schizophrenia who were partial responders to clozapine, is consistent with our previous report which had the same design but was of somewhat shorter duration (Anil Yagcioglu et al., 2005), with the exception that we found that improvement in psychopathology after the addition of placebo was superior to risperidone. A second paper from our double-blind, randomized trial has been submitted which showed that improvement in cognition with placebo was often, but not always, greater than that with risperidone as well. Honer et al. explicitly stated that their results were consistent with ours. We proposed, based upon my hypothesis that more potent blockade of 5-HT2A than D2 receptors contributed to the beneficial effects of clozapine (Meltzer et al., 1989), that the reason for the superior response to placebo in our trial was that risperidone, by adding D2 receptor blockade to clozapine, interfered with the beneficial effects of being part of a clinical study with its increased clinical contact and supportive nature. The results of our study and that of Honer contrast with a third study (Josaissen et al., 2005), which found risperidone addition improved psychopathology more than placebo.

The New England Journal of Medicine editorial from John M. Davis is a very disappointing commentary on this important confirmation of our research in a key area because it has a number of serious errors in fact and gratuitous criticism of industry-funded studies which, at least in this case, are easily refutable. Davis stated that our study and that of Josiassen et al. were industry-funded, as contrasted with the Honer et al. study, which was funded by the Stanley Medical Research Foundation, of which Davis has been a long-time adviser. The implication is clear that the industry-funded studies are biased. Davis then continues his effort to raise doubt about industry-funded studies by contrasting the results of his several meta-analyses of industry-funded clinical trials, which found advantages of atypical over typical antipsychotic drugs, with that of the NIMH-funded CATIE study, which did not (Lieberman et al., 2005).

In fact, our study was clearly marked as having been funded by the Stanley Medical Research Foundation, the William K. Warren Medical Research Foundation, and the Janssen Pharmaceutical Company, manufacturer of risperidone. The Josaissen study was industry-supported. Instead of evaluating the three studies for their merits, or even reading the paper carefully (in the case of our study), Davis would have us doubt their validity because they were industry-supported. This is unacceptable in my view. His call for more industry and non-industry studies is a smoke screen for his real message, that industry-funded studies are biased. I and my coauthors can vouch for the fact that none of the three funders of our pioneering research exerted the least influence on the design, performance, or write-up of our work. Janssen was informed of the results of the study as called for in our contract and made no effort, nor should it have, to restrain or modify the message. This, in fact, has been consistent with my entire experience with major pharma and biotech companies. If Professor Davis has had more negative experiences with industry in this regard, he should make them public. As it is, he offers incorrect information to raise doubts about industry-funded research at a time when it is already under attack in the area of clinical trials and when continued investment on its part in clinical research in psychiatry is urgently needed, in my view. What we need is more thoughtful consideration of the merits and shortcomings of all clinical trials regardless of funding source. The clinical investigators and funder of the CATIE trial are now finding that merely because their study was government-funded, it is not being taken by many as the last word in informing us about antipsychotic drug treatment in schizophrenia.

Our paper (Honer et al., 2006) and the associated editorial by Dr. John M. Davis (Davis, 2006) concerning augmentation of risperidone with clozapine drew some commentary in this Forum, and recently, three letters to the Editor of the New England Journal of Medicine. The April 27 issue of the NEJM also includes our response, and a response from Dr. Davis. The first of the letters, from Grass and colleagues (Grass et al., 2006) concerns the broader issues of the confidence with which we can conclude that risperidone augmentation of clozapine offers no benefit, and the degree to which the results of this approach to antipsychotic polypharmacy can be generalized to other combinations of antipsychotic drugs. Basically, our conclusion in the paper is that the difference between risperidone and placebo augmentation of clozapine is unlikely to be associated with a moderate-to-large effect size, such as would be observed with switching a group of patients from typical antipsychotics to clozapine. Smaller differences cannot be excluded. However, as clarified by Dr. Davis in the recent issue, one of the two previous, smaller placebo-controlled studies showed relative benefit for placebo versus risperidone augmentation, at least for positive symptoms (Anil Yagcioglu et al., 2005). The NEJM letters from Meltzer and colleagues (Meltzer et al., 2006) and from Gerson (Gerson, 2006) concern the Davis editorial which accompanied our paper. Dr. Meltzer’s concerns about the editorial are also presented in his commentary in the Forum, and Dr. Davis has graciously apologized for his errors in the current response in the Journal, and clarified that monitoring of white cell counts provides a safe approach for patients taking this medication.

We still face the broader issue of antipsychotic polypharmacy, which appears reasonably prevalent despite a very small evidence base. Our trial was initially designed with the hope that risperidone, being a high-affinity dopamine D2 antagonist, would be an optimum drug to augment the low D2 affinity of clozapine. This was not the case, and strictly speaking our results cannot be generalized beyond this combination of medications. Much larger studies would be needed if a non-inferiority design were to be used. For example, subjects currently treated with antipsychotic polypharmacy could be randomized to continuation or to substitution with placebo for all but one antipsychotic drug. A preliminary, uncontrolled study indicated this strategy was successful in most, but not all cases (Suzuki et al., 2004). Perhaps new findings concerning the consequences of antipsychotic polypharmacy for cognitive function (Kawai et al., 2006) and the economic costs (Stahl and Grady, 2006) will also contribute to improving evidence-based practice.